Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus

The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary neuronalβ-secretase,β-site amyloid precursor protein cleaving enzyme 1(BACE1).The anticoagulant activity of heparin has,however,precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic.Here,a glycosaminoglycan extract,composed predominantly of 4-sulfated chondroitin sulfate,has been isolated from Sardina pilchardus,which possess the ability to inhibit BACE1(IC50[half maximal inhibitory concentration]=4.8μg/mL),while displaying highly attenuated anticoagulant activities(activated partial thromboplastin time EC50[median effective concentration]=403.8μg/mL,prothrombin time EC50=1.3 mg/mL).The marine-derived,chondroitin sulfate extract destabilizes BACE1,determined via differential scanning fluorimetry(ΔTm–5°C),to a similar extent as heparin,suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action,which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.

Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.

深圳福田红树林弧边招潮蟹的行为习性观察研究

弧边招潮蟹(Uca arcuata)是红树林的生态系统工程师,然而我国对弧边招潮蟹的研究相对薄弱。为了研究弧边招潮蟹的行为习性,作者于2013年7—9月在深圳福田红树林自然保护区,借助望远镜观察了弧边招潮蟹的11种行为。结果表明:弧边招潮蟹主要栖息于潮沟两侧的林缘生境,和大多数招潮蟹一样,弧边招潮蟹的大部分时间(69%)用于觅食(进食+边走边食),其次是站立(11%),用于求偶的时间最少(0.23%)。弧边招潮蟹的繁殖期有延长的现象,观察到的交配时间比以往的研究要短。除记录的11种行为之外,还观察到弧边招潮蟹的探洞、边走边食边挥舞大螯、“投降”等行为,表明弧边招潮蟹的行为较复杂。弧边招潮蟹的短距离迁移能力较强,单次迁移距离可达30 m以上。生境、性别、时间等因素对弧边招潮蟹的行为影响较大,手性和潮汐的影响较小。污染较严重的生境中弧边招潮蟹用于觅食和洞穴行为的时间均显著减少,导致其生物扰动作用减弱,从而不利于红树林生态系统的健康。本文丰富了弧边招潮蟹的研究,对全面、深入了解红树林生态系统,及红树林的管理和保护有重要的参考价值。

On Splitting Training and Validation Set:A Comparative Study of Cross-Validation,Bootstrap and Systematic Sampling for Estimating the Generalization Performance of Supervised Learning

Model validation is the most important part of building a supervised model.For building a model with good generalization performance one must have a sensible data splitting strategy,and this is crucial for model validation.In this study,we con-ducted a comparative study on various reported data splitting methods.The MixSim model was employed to generate nine simulated datasets with different probabilities of mis-classification and variable sample sizes.Then partial least squares for discriminant analysis and support vector machines for classification were applied to these datasets.Data splitting methods tested included variants of cross-validation,bootstrapping,bootstrapped Latin partition,Kennard-Stone algorithm(K-S)and sample set partitioning based on joint X-Y distances algorithm(SPXY).These methods were employed to split the data into training and validation sets.The estimated generalization performances from the validation sets were then compared with the ones obtained from the blind test sets which were generated from the same distribution but were unseen by the train-ing/validation procedure used in model construction.The results showed that the size of the data is the deciding factor for the qualities of the generalization performance estimated from the validation set.We found that there was a significant gap between the performance estimated from the validation set and the one from the test set for the all the data splitting methods employed on small datasets.Such disparity decreased when more samples were available for training/validation,and this is because the models were then moving towards approximations of the central limit theory for the simulated datasets used.We also found that having too many or too few samples in the training set had a negative effect on the estimated model performance,suggesting that it is necessary to have a good balance between the sizes of training set and validation set to have a reliable estimation of model performance.We also found that systematic sampling method such as K-S and SPXY generally had very poor estimation of the model performance,most likely due to the fact that they are designed to take the most representative samples first and thus left a rather poorly representative sample set for model performance estimation.

Phosphorylation‐dependent Traffcking of Plasma Membrane Proteins in Animal and Plant Cells

In both unicellular and multicellular organisms, transmembrane （TM） proteins are sorted to and retained at specific membrane domains by endomembrane trafficking mechanisms that recognize sorting signals in the these proteins. The trafficking and distribution of plasma membrane （PM）-localized TM proteins （PM proteins）, especially of those PM proteins that show an asymmetric distribution over the PM, has received much attention, as their proper PM localization is crucial for elementary signaling and transport processes, and defects in their localization often lead to severe disease symptoms or developmental defects. The subcellular localization of PM proteins is dynamically regulated by post-translational modifications, such as phosphorylation and ubiquitination. These modificaitons mostly occur on sorting signals that are located in the larger cytosolic domains of the cargo proteins. Here we review the effects of phosphorylation of PM proteins on their trafficking, and present the key examples from the animal field that have been subject to studies for already several decades, such as that of aquaporin 2 and the epidermal growth factor receptor. Our knowledge on cargo trafficking in plants is largely based on studies of the family of PIN FORMED （PIN） carriers that mediate the efflux of the plant hormone auxin. We will review what is known on the subcellular distribution and trafficking of PIN proteins, with a focus on how this is modulated by phosphorylation, and identify and discuss analogies and differences in trafficking with the well-studied animal examples.

Dissecting the Native Architecture and Dynamics of Cyanobacterial Photosynthetic Machinery

The structural dynamics and flexibility of cell membranes play fundamental roles in the functions of the cells, i.e., signaling, energy transduction, and physiological adaptation. The cyanobacterial thylakoid membrane represents a model membrane that can conduct both oxygenic photosynthesis and respiration simultaneously. In this study, we conducted direct visualization of the global organization and mobility of photosynthetic complexes in thylakoid membranes from a model cyanobacterium, Synechococcus elongatus PCC 7942, using high-resolution atomic force, confocal, and total internal reflection fluorescence microscopy. We visualized the native arrangement and dense packing of photosystem I （PSI）, photosystem II （PSlI）, and cytochrome （Cyt） befwithin thylakoid membranes at the molecular level. Furthermore, we func- tionally tagged PSI, PSlI, Cyt bef, and ATP synthase individually with fluorescent proteins, and revealed the heterogeneous distribution of these four photosynthetic complexes and determined their dynamic features within the crowding membrane environment using live-cell fluorescence imaging. We characterized red light-induced clustering localization and adjustable diffusion of photosynthetic complexes in thylakoid membranes, representative of the reorganization of photosynthetic apparatus in response to environmental changes. Understanding the organization and dynamics of photosynthetic membranes is essential for rational design and construction of artificial photosynthetic systems to undarpin bioenergy development. Knowledge of cyanobacterial thylakoid membranes could also be extended to other cell membranes, such as chloroplast and mitochondrial membranes.

The evolutionary consequences of selfish genetic elements

The traditional view of the genome was once that it is broadly cooperative, with all genes working together amicably to improve the success of the individual as a whole. Benefits to the individual, after all, benefit all the component genes, as fair Mendelian inheritance ensures that all the genes and alleles a parent carries are equally likely to be inherited by an offspring. However, more detailed studies of inheritance have shown that this rosy view of cooperation within the genome is untrue. Instead, many genes act selfishly, manipulating gametogenesis to bias transmission in their favor （Butt and Trivers 2006）. This increases their representation in offspring at a cost to the fitness of the individual and the cooperative genes.

Cryoelectron Microscopy Delineates the In Situ Structure of the Thylakoid Network

Photosynthesis is conceivably the most important biological process on Earth.By performing oxygenic photosynthesis,cyanobacteria,algae,and plants can use solar energy to power their metabolism and produce sugars and oxygen for life on the planet.These photosynthetic organisms have evolved a specialized intracellular membrane system,the thylakoid membrane,inside the cytoplasmic membrane to carry out the reactions of photosynthesis.

Preliminary investigation on rodent–ectoparasite associations in the highlands of Tigray, Northern Ethiopia:implications for potential zoonoses

We studied associations between rodents and their arthropod ectoparasites in crop fields and household compounds in the highlands of Tigray,Northern Ethiopia.Ectoparasite infestation indices,such as percent infestation,mean abundance,prevalence and host preferences,were calculated for each taxon.In total,172 rodents from crop fields and 97 from household compounds were trapped.Rodent species and numbers trapped from the crop fields and household compounds were Mastomys awashensis(Lavrenchenko,Likhnova&Baskevich,1998)(88 and 44),Arvicanthis dembeensis(Ruppel,1842)(63 and 37)and Acomys sp.(21 and 16),respectively.A total of 558 insects and acarids(belonging to 11 taxa)were recovered from the rodents trapped in the crop fields,and 296 insects and acarid(belonging to 6 taxa)from the rodents trapped in the household compounds.Approximately 66%of the rodents trapped from the crop fields and 47%of those trapped from the household compounds were infested with ectoparasites.Laelaps sp.(64.9%)and Xenopsylla sp.(20.6%)comprised the highest proportion of the ectoparasites recovered in the crop fields,and the same ectoparasites,but in reverse order,comprised the highest proportions in the household compounds(Xenopsylla[50.3%]and Laelaps sp.[29%]).Our study revealed that crop fields and household compounds in the highlands share similar rodents and several ectoparasites.Furthermore,at least 1 of the rodent species and some of the ectoparasites identified in this study were reported to have posed medical and veterinary threats in other parts of Ethiopia and neighboring countries.

一种快速分析细胞内脂质沉积的方法

目的:建立快速分析细胞内脂质沉积的方法。方法:以油酸刺激人肝癌细胞形成脂质沉积,利用BODIPY 493/503染色细胞内脂滴,在Matlab环境下以荧光图像分析技术分析脂滴荧光强度;采用蛋白印迹法分析脂质沉积标志蛋白——脂滴表面蛋白Adipophilin的蛋白水平,以及采用实时荧光定量PCR法检测Adipophilin的基因表达水平,以验证荧光图像分析技术的可靠性。结果:利用荧光图像分析技术建立了快速定量脂质沉积的方法,结果显示该方法下400μmol/L油酸显著提高细胞内脂质含量达1.41倍,与标志蛋白Adipophilin的蛋白水平增高2.07倍,基因表达水平增高1.53倍一致。结论:该可快速定量细胞内脂质沉积水平,且结果可靠。

Relationships between blood leukocyte mitochondrial DNA copy number and inflammatory cytokines in knee osteoarthritis

Osteoarthritis(OA)is a degenerative articular disorder manifested by cartilage destruction,subchondral sclerosis,osteophytes,and synovitis,resulting in chronic joint pain and physical disability in the elderly.The purpose of this study was to investigate mitochondrial DNA copy number(mtDNACN)and inflammatory cytokines in primary knee OA patients and healthy volunteers.A total of 204 knee OA patients and 169 age-matched healthy volunteers were recruited.Their relative blood leukocyte mtDNACN was assessed by quantitative real-time polymerase chain reaction(qRT-PCR),and ten inflammatory cytokines in their plasma were detected by multiplex immunoassay.Blood leukocyte mtDNACN in the OA group was significantly lower than that in the control group.Leukocyte mtDNACN in the control group was negatively correlated with their age(r=−0.380,P<0.0001),whereas mtDNACN in the OA group was positively correlated with their age(r=0.198,P<0.001).Plasma interleukin-4(IL-4)and IL-6 were significantly higher in the knee OA group than in the control group.The plasma IL-6 level was positively correlated with blood leukocyte mtDNACN in the OA group(r=0.547,P=0.0014).IL-5 showed as a major factor(coefficient 0.69)in the second dimension of principle components analysis(PCA)-transformed data and was significantly higher in the OA group(P<0.001)as well as negatively correlated with mtDNACN(r=−0.577,P<0.001).These findings suggest that elevation of plasma IL-4 and IL-6 and a relative reduction in mtDNACN might be effective biomarkers for knee OA.IL-5 is a plausible factor responsible for decreasing blood leukocyte mtDNACN in knee OA patients.

Sex-specific sterility caused by extreme temperatures is likely to create cryptic changes to the operational sex ratio in Drosophila virilis

Climate change is increasing the frequency and severity of short-term heat shocks that threaten the persistence of natural populations.However,most work addressing the evolutionary consequences of anthropogenic environmental change has focused on natural selection,with less attention paid to the impacts on sexual selection.The conditions under which sexual selection operates is a topic of debate,but a generally observed pattern is that the oper-ational sex ratio(OSR)of a population is key to determining both the extent of competition for fertilizations and the scope for mate choice(Weir et al.2011)

Photosynthesis in Phytoplankton: Insights from the Newly Discovered Biological Inorganic Carbon Pumps

Aquatic C02 assimilation results in storage in the oceans of〜24%of anthropogenic C02(〜40 petagrams per annum)released into the atmosphere and makes significant contributions to the global carbon cycle.These processes are executed predominantly in phytoplankton in the oceans(including cyanobacteria),which account for nearly 50%of global primary productivity(~50 gigatons per annum)(Field et al.,1998).